Accumulation of the amyloid-beta (alphabeta) plaque in the cerebral cortex is a critical event in the pathogenesis of Alzheimer’s disease. alphabeta peptide is generated by proteolytic cleavage of the β-amyloid protein precursor (APP) at beta- and gamma-sites by proteases. The long-sought β-secretase was recently identified by several groups independently and designated beta-site APP cleaving enzyme (BACE) and aspartyl protease 2 (Asp2) (1-4). BACE/Asp2 is a novel transmembrane aspartic protease and co-localizes with APP. A BACE homolog was recently cloned and designated BACE2, Asp1, DRAP (for Down region aspartic protease), and memapsin 1 (4-9). BACE2 also cleaves APP at b-site and at a different site within alphabeta (8). BACE2 locates on chromosome 21q22.3, the so-called ‘Down critical region’, suggesting that BACE2 and alphabeta may also contribute to the pathogenesis of Down syndrome (6,7)